Article date: 1991/11/1
PubMed ID: 1655982
Journal name: Journal of neurochemistry (ISSN: 0022-3042)
Neuroactive steroids, in particular 3 alpha-hydroxypregnanes, are allosteric modulators of the gamma-aminobutyric acidA (GABAA) receptor. Regionally selective expression of receptor subunit subtypes may account for differential responsiveness of tissues to GABAergic inhibition and neurosteroid modulatory effects. The effect of 5 alpha-pregnan-3 alpha-ol-20-one (epiallopregnanolone) on heterotropic cooperativity on the GABAA receptor complex has been studied in three subtypes of expressed recombinant human receptors and in rat brain and spinal cord. Steroid potentiation of [3H]flunitrazepam binding was greatest for the alpha 3 beta 1 gamma 2 receptor complex, whereas alpha 1 beta 1 gamma 2 and alpha 2 beta 1 gamma 2 complexes showed less than 100% enhancement in binding. Previous studies suggest that the spinal cord is devoid of alpha 1, whereas cerebellum is rich in alpha 1 subunits. Correspondingly, a differential enhancement of [3H]flunitrazepam binding in spinal cord (51%) versus cerebellum (28%) was also observed. The structure of neuroactive steroids is important in determinikng the extent of neuromodulatory activity. The 5 beta-pregnanes,5 beta-pregnan-3 alpha-ol-20-one (epipregnanolone) and 5 beta-pregnan-3 alpha,21-diol-20-one (5 beta-tetrahydrodeoxycorticosterone), were both less potent than their corresponding 5 alpha derivatives. A 3 alpha hydroxyl group is essential for neuromodulatory activity in the expressed receptors, as demonstrated by the observation that 5 alpha-pregnan-3 beta-ol-20-one (allopregnanolone) and 4-pregnen-3, 20-dione (progesterone) were both inactive.(ABSTRACT TRUNCATED AT 250 WORDS)
Author List: Lan N C, Gee K W, Bolger M B, Chen J S
Publication Types: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.
Substances mentioned in the article: Macromolecular Substances; Pregnanediones; Pregnanes; Receptors, GABA-A; Recombinant Proteins; Muscimol; Progesterone; Flunitrazepam; alphaxalone;
Mesh terms: Allosteric Regulation; Animals; Binding, Competitive; Brain/metabolism; Cell Line; Flunitrazepam/metabolism; Humans; Kinetics; Macromolecular Substances; Muscimol/metabolism; Pregnanediones/pharmacology; Pregnanes/pharmacology; Progesterone/pharmacology; Rats; Receptors, GABA-A/drug effects; Recombinant Proteins/drug effects; Spinal Cord/metabolism; Transfection;